At the CMC Strategy Forum on Quality by Design (QbD) in July, discussions focused on an unlikely subject: noncritical process
parameters. The core question was, How much regulatory oversight do they require?
The question about noncritical parameters arose in a broader discussion about how companies handle their manufacturing control
strategy in the context of QbD. For example, according to the ICH Q8 guidance, companies may make postapproval movements within
a design space without regulatory oversight. But does that apply equally on the edges of a design space?
Noncritical parameters, which may not be captured in the design space, also present ambiguity.
At the meeting, industry professionals argued that companies should not be required to include extensive information about
noncritical parameters in their regulatory filings, and instead should have the flexibility to manage these parameters through
their internal quality systems.
Regulators, however, had a different view. They acknowledged that critical and noncritical parameters should be treated differently
from a regulatory point of view, but did not want to completely lose the ability to monitor any of them.
"If we take noncritical process parameters out of the group of things that are visible to the agency, that raises concerns,"
said Steven Kozlowski, director of the FDA's Office of Biotechnology Products. "We need a way of having companies include
some detail on change control for noncritical parameters, such that if a big change is made, the company would have to involve
IS THAT PARAMETER REALLY NONCRITICAL?
Kozlowski's concern stems from uncertainty that risk assessments used to classify parameters are accurate, particularly if
those assessments are carried out early in product development.
"The understanding of criticality evolves during development and the product lifecycle," Kozlowski said. "If some adverse
event arises later that you think may be related to a potential noncritical quality attribute, then you should revisit it."
On that point, industry members agreed. "There seems to be a misconception that noncritical attributes disappear," said Rohin
Mhatre, vice president of biopharmaceutical development at Biogen Idec. "If you see random changes in a quality attribute,
you would examine all potential triggers, including parameters not deemed critical."
REVIEW BRANCH OR INSPECTORATE?
Minimizing the data filed about noncritical process parameters would shift their oversight from regulatory agencies' review
branches, which approve applications, to the compliance branches, which inspect manufacturing sites.
For the industry, that shift would be preferable. "We want to get to the point where regulators are confident with how we're
handling our quality management throughout the product lifecycle, but I'd prefer to have that linkage occur between the review
and compliance branches," said John Towns, senior director of CMC regulatory affairs at Eli Lilly. "I would prefer to handle
it in inspection."
"But inspections only last a week or so," cautioned Kozlowski. "That is not a big slice in time."